This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. MS attacks occur less frequently during pregnancy, which is likely due to the increased production of steroidal sex hormones. Similarly, the severity of experimental autoimmune encephalomyelitis (EAE), an MS-like disease in mice, is also diminished during pregnancy. In mice, steroidal estrogens can inhibit anti-myelin helper T-lymphocyte responses and suppress EAE. In some women with MS, steroidal estrogens can decrease the number of demyelinating lesions in the CNS. Nevertheless, steroidal estrogens have a limited therapeutic potential because their long-term use increases the risk for hormone-related cancers. Phytoestrogens have potent estrogen-agonist activity in bone and cardiovascular tissues, yet lack activity in breast and uterine tissues. Isoflavones derived from soybeans are a rich source of phytoestrogens. Genistein, daidzein, and glycitein are the major isoflavones derived from soy The main objectives of this proposal are: (1) To identify the soy-isoflavones with the greatest ability to suppress EAE, (2) To determine whether soy isoflavone-mediated inhibition of TNF-alpha and suppression of EAE are dependent on signaling through ER-beta, (3) To determine which immune cells express ER-beta and whether transcription of immunologically relevant genes is regulated by soy isoflavones.